rs779430325

Variant names:

• chr1-156861136-C-G
• rs779430325
• NM_002529.4:c.202C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-156861136-C-G
• chr1-156861136-C-T
• chr1-156861136-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002529.4(NTRK1):​c.202C>G​(p.Leu68Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,423,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L68L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.21
• Publications: 1 publications found

Genes affected

NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

NTRK1 Gene-Disease associations (from GenCC):

• hereditary sensory and autonomic neuropathy type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31340677).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002529.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	NM_002529.4	MANE Select	c.202C>G	p.Leu68Val	missense	Exon 1 of 17	NP_002520.2
	NTRK1	NM_001012331.2		c.202C>G	p.Leu68Val	missense	Exon 1 of 16	NP_001012331.1	P04629-2
	NTRK1	NM_001007792.1		c.123-3218C>G		intron	N/A	NP_001007793.1	P04629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.202C>G	p.Leu68Val	missense	Exon 1 of 17	ENSP00000431418.1	P04629-1
	NTRK1	ENST00000368196.7	TSL:1	c.202C>G	p.Leu68Val	missense	Exon 1 of 16	ENSP00000357179.3	P04629-2
	NTRK1	ENST00000358660.3	TSL:2	c.202C>G	p.Leu68Val	missense	Exon 1 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000281 AC: 4 AN: 1423852 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706122

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.00 AC: 0 AN: 41654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25588

East Asian (EAS) AF: 0.00 AC: 0 AN: 38578

South Asian (SAS) AF: 0.00 AC: 0 AN: 82492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5398

European-Non Finnish (NFE) AF: 0.00000365 AC: 4 AN: 1096802

Other (OTH) AF: 0.00 AC: 0 AN: 59064

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary insensitivity to pain with anhidrosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.21
Sift	Benign	0.30	T
Sift4G	Benign	0.82	T
Polyphen		0.0020	B
Vest4		0.30
MutPred		0.29		Loss of disorder (P = 0.083)
MVP		0.98
MPC		0.87
ClinPred		0.45	T
GERP RS		3.9
PromoterAI		0.084	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.31
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs779430325; hg19: chr1-156830928;